End stage renal disease is one of the leading causes of death and chronic disability in the United States. Though it can be managed by either dialysis or by renal transplantation, it is widely recognized that successful renal transplantation is associated with a better quality of life and better chances of rehabilitation. Currently the major limitation to the successful application of renal transplantation (other than a shortage in the supply of donor kidneys) is the occurrence of acute and chronic rejection, each of which leads to loss of about one-fifth of kidneys over the first five years following renal transplantation. While there have been major advances in the management of acute rejection over the past ten years nationwide one year renal allograft survival has not improved much over the past five years. There has been little change in the rate of graft loss after one year, due to chronic rejection, since the beginning of the transplant era in 1960. A major factor limiting improvement in immunosuppressive therapies for renal transplantation has been the lack of a large multicenter clinical trial group to evaluate proposed new agent and new regimens in a timely factor. Given a failure rate of no more than 15% - 20% per year, studies of proposed new therapies will require numbers of subjects approaching 2000 to detect clinically significant differences in outcome between treatment groups, if one requires statistical significance at the 0.05 level and a power of at least 0.80. Even the largest centers lack sufficient patients to complete studies of new therapies in periods less than several years. NIH now proposes to sponsor the development of such a multicenter Cooperative Clinical Trial Group in Transplantation. In this application, the University of Iowa Transplant Service proposes to join this NIH sponsored trial group. We propose that to make efficient use of limited patient and fiscal resources, the study design should allow for simultaneous factorial randomized to different stages of therapy, such as induction and maintenance immunosuppression therapies, and sequential randomization to other therapies such as management of acute rejection episode and management of long term immunosuppression. To initiate this study group we propose a series of trials, using the above design, to determine whether a) addition of induction therapy with antilymphocyte globulin, or b) substitution of RS-61443 for azathioprine in baseline "triple immunosuppression" will increase the fraction of surviving grafts or decrease the frequency of severe rejection episodes, c) whether the anti-T-cell receptor monoclonal antibody T10B9.1A-31 will be as effective as OKT3 in management of severe acute rejection and will be associated with a reduced severity of "first-dose" side effects, and whether stopping steroid therapy (while continuing cyclosporine and either azathioprine or RS-61443) in renal allograft recipients who have not experienced a severe rejection within the first six months following transplant will improve the risk factors for atherosclerotic vascular disease (hypertension, hyperlipidemia glucose intolerance, obesity) without an increase in late rejection episodes or loss of renal grafts.